Coagulation factor V is located at a critical regulatory step in hemostasis. Genetic deficiency of factor V results in a severe congenital bleeding disorder (parahemophilia). In contrast, a factor V "gain of function" mutation leading to protein C resistance (factor V Leiden (R506Q) is the most common genetic risk factor for thrombosis. This proposal will use transgenic mouse models to explore the function of factor V in vivo and its role in disease pathogenesis. In preliminary studies, factor V deficient mice have been generate by gene targeting. Surprisingly, about + of the factor V null mice are lost during early embryogenesis, with the remainder dying of hemorrhage within a few hours of birth. Gene targeting has also been used to insert the murine homologue of R506Q into the endogenous mouse factor V gene. Mice homozygous for this mutation exhibit severe spontaneous thrombosis. The Specific Aims of this proposal will further examine the bleeding and thrombotic phenotypes of these murine models for human disease. Tissue-specific transgene expression will be used to characterize the relative contributions of the distinct plasma and platelet factor V pools to normal hemostasis. The previously unrecognized role of coagulation components in early mammalian development will also be explored by analysis of these and other genetically engineered mice. Finally, the relative contributions of platelet and plasma factor V pools to thrombophilia, as well as the interaction between APC resistant factor V and other coagulation components, will be investigated. These studies should yield valuable new information concerning the biologic functions of factor V and the pathogenesis of thrombosis associated with APC resistance. In addition, the transgenic mice generated from these studies may provide powerful animal models for the development of novel anticoagulant therapies.